Extended-release topiramate capsules

ABSTRACT

An extended-release topiramate capsule that includes a capsule shell containing a single population of coated particles; wherein each coated particle includes a core and a coating thereon; wherein each particle core includes a homogeneous mixture comprising topiramate throughout its core; and wherein the coating includes one or more release controlling agent(s).

CONTINUING APPLICATION DATA

This application is a continuation of U.S. patent application Ser. No.13/847,042, filed Mar. 19, 2013, which claims the benefit of U.S.Provisional Application Ser. No. 61/779,576, filed Mar. 13, 2013, andalso claims the benefit of U.S. Provisional Application Ser. No.61/788,880, filed Mar. 15, 2013, each of which is incorporated byreference herein.

BACKGROUND

The pharmaceutical industry employs a variety of dosage formulations fororally administering medicinal agents to patients. Typical formulationsfor oral administration include liquid solutions, emulsions, orsuspensions, as well as solid forms such as capsules or tablets (as usedherein, the term “tablet” means any shaped and compressed solid dosageform, including caplets).

Efficacy of a drug product often depends on patient compliance with adosing schedule. Therefore, one per day, extended-release, dosages havebetter efficacy over the long term than multidose regimens.

SUMMARY

The present disclosure provides solid dosage formulations of topiramate[2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate],particularly capsules, containers including such capsules, and methodsof dosing.

In one embodiment, the present disclosure provides an extended-releaseformulation that is dosed once-per-day, in the form of a capsule.

In one embodiment, the present disclosure provides an extended-releasetopiramate capsule that includes a capsule shell and a single populationof coated particles contained within the capsule shell, wherein eachcoated particle includes a core and a coating thereon. In certainembodiments, the particles, whether coated or uncoated, are spherical.

Each particle core includes a homogeneous mixture including topiramatethroughout the core. In certain embodiments, each particle core alsoincludes a filler and/or a binder (preferably, both a filler and abinder) in the homogeneous mixture.

The coating includes a release controlling agent. In certainembodiments, the coating also includes a pore former and/or aplasticizer.

In one embodiment, an extended-release topiramate capsule is providedthat includes: a capsule shell containing a single population of coatedparticles; wherein each coated particle includes a core and a coatingthereon; wherein each particle core includes a homogeneous mixturethroughout its core, the mixture including: 40 wt-% to 50 wt-% oftopiramate, based on the total weight of an uncoated particle core; 45wt-% to 55 wt-% of one or more filler(s), based on the total weight ofan uncoated particle core; and 3 wt-% to 7 wt-% of one or morebinder(s), based on the total weight of an uncoated particle core;wherein the coating includes: 55 wt-% to 65 wt-% of one or more releasecontrol agent(s), based on the total weight of the coating; 20 wt-% to25 wt-% of one or more pore former(s), based on the total weight of thecoating; and 10 wt-% to 20 wt-% of one or more plasticizer(s), based onthe total weight of the coating; wherein the particles are coated in anamount sufficient to provide a (coating) weight gain of 8% to 14%.

As used herein, the terms “topiramate active agent” and “active agent oftopiramate” and “topiramate” are synonymous and are used interchangeablythroughout the specification to refer to the compound2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate.Included within these terms are also pharmaceutically acceptable saltsthereof as well as polymorphs, solvates, hydrates, dehydrates,co-crystals, anhydrous, and amorphous forms thereof.

The term “extended-release” means release of an active agent over aperiod of time, which is much longer than the release from an immediaterelease formulation, which usually releases more than 80% of the activeagent in 60 minutes or less.

The term “therapeutically effective amount” as used herein means thatamount of active compound that elicits the biological or medicinalresponse in a tissue, system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation and/or prevention of the symptoms of the conditionbeing treated.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims. Suchterms will be understood to imply the inclusion of a stated step orelement or group of steps or elements but not the exclusion of any otherstep or element or group of steps or elements. By “consisting of” ismeant including, and limited to, whatever follows the phrase “consistingof” Thus, the phrase “consisting of” indicates that the listed elementsare required or mandatory, and that no other elements may be present. By“consisting essentially of” is meant including any elements listed afterthe phrase, and limited to other elements that do not interfere with orcontribute to the activity or action specified in the disclosure for thelisted elements. Thus, the phrase “consisting essentially of” indicatesthat the listed elements are required or mandatory, but that otherelements are optional and may or may not be present depending uponwhether or not they materially affect the activity or action of thelisted elements.

The words “preferred” and “preferably” refer to embodiments of thedisclosure that may afford certain benefits, under certaincircumstances. However, other embodiments may also be preferred, underthe same or other circumstances. Furthermore, the recitation of one ormore preferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the disclosure.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. Thus, for example, a particle core that comprises“a” binder can be interpreted to mean that the particle core includes“one or more” binders. Similarly, a coating comprising “a” pore formercan be interpreted to mean that the composition includes “one or more”pore formers.

As used herein, the term “or” is generally employed in its usual senseincluding “and/or” unless the content clearly dictates otherwise.

The term “and/or” means one or all of the listed elements or acombination of any two or more of the listed elements (e.g., preventingand/or treating an affliction means preventing, treating, or bothpreventing and treating an affliction).

Also herein, all numbers are assumed to be modified by the term “about”and preferably by the term “exactly.” As used herein in connection witha measured quantity, the term “about” refers to that variation in themeasured quantity as would be expected by the skilled artisan making themeasurement and exercising a level of care commensurate with theobjective of the measurement and the precision of the measuringequipment used.

Also herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range as well as the endpoints (e.g., 1to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Herein, “up to” anumber (e.g., up to 50) includes the number (e.g., 50).

The above summary of the present disclosure is not intended to describeeach disclosed embodiment or every implementation of the presentdisclosure. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present disclosure provides solid dosage formulations of topiramate[2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate]. Suchsolid dosage formulations are extended-release once-per-day dosagecapsules (i.e., designed for administration once per day).

In one embodiment, the present disclosure provides an extended-releasetopiramate capsule that includes a capsule shell and a single populationof coated particles contained within the capsule shell. In this context,“a single population” means that all the particles in one capsule arethe same (within reasonable manufacturing variability) with respect tocomposition. In this context, “same” means the particles in one capsuleare made in a single batch process or in multiple batches usingidentical processes.

The use of a single population of particles in any one capsule providessignificant advantages from a manufacturing (e.g., quality and cost)perspective. For example, different populations of particles (e.g.,beads), having different compositions, do not need to be manufacturedfor one product.

Furthermore, in certain embodiments, the capsules of the presentdisclosure do not include an immediate release component in anysignificant amount. Typically, capsules of the present invention arefree of an immediate-release component.

Each coated particle includes a core and a coating thereon. In certainembodiments, the particles, whether coated or uncoated, are spherical,as defined in greater detail below.

Each particle core includes a homogeneous mixture including topiramatethroughout the core. In certain embodiments, each particle core alsoincludes a filler and/or a binder (preferably, both a filler and abinder) in the homogeneous mixture.

The coating on each core includes a release controlling agent. Incertain embodiments, the coating also includes a pore former and/or aplasticizer.

In one embodiment, the present disclosure provides a solid dosageformulation that includes a capsule including core particles with acoating thereon. The core particles include the active agent. The coreparticles can also include a filler and/or a binder (preferably, both afiller and a binder). The coating includes a release-controlling agent.The coating can also include a pore former and/or a plasticizer.

In certain embodiments, the particles, whether coated or uncoated, arespherical. In this context, the term “spherical” refers to particlesthat are generally rounded by visual inspection. They may or may not beperfectly spherical. A representative population of spherical particles(i.e., beads) typically has an average sphericity of at least 0.7. Incertain embodiments, the average sphericity of a representativepopulation of particles is at least 0.75, and in certain embodiments atleast 0.8. A preferred sphericity is 0.8. Sphericity can be determinedby use of a digital microscope and a two-dimensional image analysissoftware (e.g., such as that by Soft Imaging System GmbH, version 5.0Build 1054).

In certain embodiments, the particle size (which is typically thediameter of a spherical particle) of the coated particles is at least500 μm (microns). In certain embodiments, the particle size of thecoated particles is up to 1300 μm. In certain embodiments, the majorityof the particles in a capsule are typically in a range of 700 μm to 1000μm.

The rate of particle dissolution is typically dependent on the coatingweight, which can be adjusted during manufacture. In certainembodiments, the particles are coated in an amount sufficient to providea weight gain of at least 2%, or at least 4%, or at least 6%, or atleast 8%, or at least 9%, or at least 10%. In certain embodiments, theparticles are coated in an amount sufficient to provide a weight gain ofup to 30%, or up to 25%, or up to 20%, or up to 15%, or up to 12%.Preferably, the particles are coated in an amount sufficient to providea weight gain of 10% to 12%. In certain embodiments, the particles arecoated in an amount sufficient to provide a weight gain of 8% to 14%.

In this context, “weight gain” is defined as the theoretical weight gainof a population of particles as a result of coating, assuming 100%coating efficiency. Thus, “weight gain” refers to coating weight gain.As an example, 100 grams of uncoated particles (e.g., beads) coated to atheoretical weight gain of 8% means that an amount of coating solutionhaving 8 grams (g) of non-volatile components, e.g., release controllingagent, pore former, and plasticizer, was applied to the uncoated beadsin a coating step, but there may be some losses in the manufacturingprocess.

Suitable active agents within the particle core include topiramate(2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate).“Topiramate” refers to2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate as wellas pharmaceutically acceptable salts of topiramate, including withoutlimitation, topiramate sodium, topiramate lithium, topiramate potassium,as well as polymorphs, solvates, hydrates, dehydrates, co-crystals,anhydrous, and amorphous forms thereof. Topiramate can be purchased fromcommercial sources. It is presently available for marketing as animmediate-release tablet product (as TOPAMAX) for certain seizureindications and migraine prophylaxis.

An amount of topiramate active agent is included within a capsule in anamount sufficient to deliver the desired dose. Alternatively stated, atherapeutically effective amount of topiramate is included within acapsule. A capsule can include a topiramate active agent in an amount ofat least 10 weight percent (wt-% or % w/w), or at least 25 wt-%, or atleast 35 wt-%, or at least 40 wt-%, or at least 44 wt-%, based on thetotal weight of an uncoated particle core. A capsule can include atopiramate active agent in an amount of up to 80 wt-%, or up to 50 wt-%,or up to 46 wt-%, based on the total weight of an uncoated particlecore. In certain embodiments, the particle cores of the capsules of thepresent disclosure include 40 wt-% to 50 wt-% topiramate active agent,based on the total weight of an uncoated particle core. In certainembodiments, the particle cores of the capsules of the presentdisclosure include 44 wt-% to 46 wt-% topiramate active agent, based onthe total weight of an uncoated particle core.

The active agent can be homogeneously mixed within a particle core thatincludes one or more fillers and/or binders. One or more stabilizers canalso be included in the particle core. Inclusion of a stabilizer mayhelp maintain the potency of topiramate over time.

Herein, for any component specified, if there are multiple grades (e.g.,molecular weights) of such component, recitation of the componentimplies any or all of such variations.

Suitable fillers for use in the particle cores include, but are notlimited to, microcrystalline cellulose, dibasic calcium phosphate,lactose, tribasic calcium phosphate, mannitol, other suitablecarbohydrates (e.g., other sugars or starches). Combinations of fillerscan be used if desired. Preferably, microcrystalline cellulose is usedas a filler (such as that available from JRS Pharma under the tradedesignation EMCOCEL 90M).

One or more fillers can be used in an amount of at least 10 wt-%, or atleast 25 wt-%, or at least 45 wt-%, or at least 48 wt-%, based on thetotal weight of the uncoated particle core. One or more fillers can beused in an amount of up to 85 wt-%, or up to 75 wt-%, or up to 55 wt-%,or up to 52 wt-%, based on the total weight of the uncoated particlecore. In certain embodiments, the particle cores of the capsules of thepresent disclosure include 45 wt-% to 55 wt-% filler(s), based on thetotal weight of an uncoated particle core. In certain embodiments, theparticle cores of the capsules of the present disclosure include 48 wt-%to 52 wt-% filler(s), based on the total weight of an uncoated particlecore.

Suitable binders for use in the particle core include, but are notlimited to, hydroxypropyl methylcellulose (i.e., hypromellose or“HPMC”), methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose,polyvinyl pyrrolidine (i.e., povidone), starch (e.g., pregelatinizedstarch), and natural gum (e.g., acacia gum, sodium alginate, guar gum,xanthan gum). Combinations of binders can be used if desired.Preferably, hydroxypropyl methylcellulose (hypromellose 2910) is used asa binder (such as that available from The Dow Chemical Company under thetrade designation METHOCEL E5 Premium).

One or more binders can be used in an amount of at least 1 wt-%, or atleast 2 wt-%, or at least 3 wt-%, or at least 4 wt-%, based on the totalweight of the uncoated particle core. One or more binders can be used inan amount of up to 10 wt-%, or up to 9 wt-%, or up to 8 wt-%, or up to 7wt-%, or up to 6 wt-%, based on the total weight of the uncoatedparticle core. In certain embodiments, the particle cores of thecapsules of the present disclosure include 3 wt-% to 7 wt-% binder(s),based on the total weight of an uncoated particle core. In certainembodiments, the particle cores of the capsules of the presentdisclosure include 4 wt-% to 6 wt-% binder(s), based on the total weightof an uncoated particle core.

Particles described herein can further include a stabilizer, preferablyin the core. Suitable stabilizers for use in the particle core include,but are not limited to, calcium hydroxide, calcium carbonate, sodiumbicarbonate, magnesium carbonate, and other alkali or alkaline earthmetal hydroxides and carbonates. Combinations of stabilizers can be usedif desired. Preferably, calcium carbonate is used as a stabilizer.

One or more stabilizers can be used in an amount of at least 1 wt-%, orat least 2 wt-%, based on the total weight of the particle core. One ormore stabilizers can be used in an amount of up to 10 wt-%, or up to 5wt-%, based on the total weight of the particle core. In certainembodiments, the particle cores of the capsules of the presentdisclosure include 2 wt-% to 10 wt-% stabilizer(s), based on the totalweight of an uncoated particle core.

Suitable release controlling agents for use in the coating on theparticle core include, but are not limited to, ethylcellulose, polyvinylacetate, polyacrylate and polymethacrylate (e.g., Ammonio MethacrylateCopolymer, Type A and Type B; Ethyl Acrylate and Methyl MethacrylateCopolymer), and copolymers thereof. Combinations of release controllingagents can be used if desired. Preferably, ethylcellulose (such as thatavailable from The Dow Chemical Company under the trade designationETHOCEL Standard 10 Premium) is used as a release controlling agent.

One or more release controlling agents can be used in an amount of atleast 45 wt-%, or at least 50 wt-%, or at least 55 wt-%, or at least 60wt-%, based on the total weight of the coating. One or more releasecontrolling agents can be used in an amount of up to 80 wt-%, or up to70 wt-%, or up to 65 wt-%, or up to 62 wt-%, based on the total weightof the coating. In certain embodiments, the particle coatings include 55wt-% to 65 wt-% release control agent(s), based on the total weight ofthe coating. In certain embodiments, the particle coatings include 60wt-% to 62 wt-% release control agent(s), based on the total weight ofthe coating.

Herein, “based on the total weight of the coating” means the totalweight of the non-volatile components of the coating (e.g., releasecontrolling agent, pore former, and plasticizer).

Pore formers that are suitable for use in the coating formulationinclude, but are not limited to, hypromellose, hydroxypropyl cellulose,methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum,sodium alginate, povidone (i.e., polyvinylpyrrolidone), crospovidone,sodium starch glycolate, croscarmellose sodium, starch (e.g.,pregelatinized starch), carbohydrates (e.g., mannitol, glucose, sucrose,fructose, mannose, galactose, sorbitol, and dextran), sodium chloride,potassium chloride, and calcium chloride. Preferred pore formers for usein the coating on the particle core include, but are not limited to,hydroxypropyl methylcellulose (“HPMC” such as hypromellose 2910 USPavailable under the trade name METHOCEL E5 Premium, METHOCEL E15Premium), carboxymethylcellulose, methylcellulose, croscarmellosesodium, povidone, sodium starch glycolate, starch (e.g., pregelatinizedstarch), alginic acid, guar gum, and polyethylene glycol. Combinationsof pore formers can be used if desired. Preferably, hydroxypropylmethylcellulose (hypromellose 2910) is used as a pore former (such asthat available from The Dow Chemical Company under the trade designationMETHOCEL E5 Premium).

One or more pore formers can be used in an amount of at least 5 wt-%, orat least 10 wt-%, or at least 15 wt-%, or at least 20 wt-%, or at least22 wt-%, based on the total weight of the coating. One or more poreformers can be used in an amount of up to 30 wt-%, or up to 26 wt-%, orup to 25 wt-%, or up to 24 wt-%, based on the total weight of thecoating. In certain embodiments, the particle coatings include 20 wt-%to 25 wt-% pore former(s), based on the total weight of the coating. Incertain embodiments, the particle coatings include 22 wt-% to 24 wt-%pore former(s), based on the total weight of the coating.

Suitable plasticizers for use in the coating on the particle coreinclude, but are not limited to, diethyl phthalate, triethyl citrate,dibutyl sebacate, polyethylene glycol, triacetin, tributyl citrate,glycerol, and propylene glycol. Combinations of plasticizers can be usedif desired. Preferably, diethyl phthalate is used as a plasticizer.

One or more plasticizers can be used in an amount of at least 5 wt-%, orat least 10 wt-%, or at least 15 wt-%, based on the total weight of thecoating. One or more plasticizers can be used in an amount of up to 30wt-%, or up to 20 wt-%, or up to 18 wt-%, based on the total weight ofthe coating. In certain embodiments, the particle coatings include 10wt-% to 20 wt-% plasticizer(s), based on the total weight of thecoating. In certain embodiments, the particle coatings include 15 wt-%to 18 wt-% plasticizer(s), based on the total weight of the coating.

The coating solution typically includes the “solids” or non-volatilecomponents (e.g., ethylcellulose, hypromellose 2910 and diethylphthalate) along with solvents, such as a mixture of alcohol and water,such that the concentration of the non-volatile components in thecoating solution is 5 wt-% to 10 wt-%. In an exemplary solution, thesolvents are dehydrated alcohol and purified water in a weight ratio of3.7:1.

Particles can be coated with a coating composition as described hereinusing conventional techniques known to one of skill in the art. Briefly,such coating techniques include bottom-spray fluid-bed coating (e.g.,Würster), top-spray fluid-bed coating, and tangential-spray fluid-bedcoating. Typically, such methods result in a coating that issubstantially uniform on each individual particle.

An amount of coated particles sufficient to deliver the desired dose maybe encapsulated into a capsule of any desirable size, for example, asize 000, 00, 0el, 0, 1, 2, 3, 4, or 5.

Components of a suitable capsule shell include, but are not limited to,hydroxypropyl methylcellulose and gelatin. Preferably, a capsule shellis a hydroxypropyl methylcellulose (HPMC) shell (e.g., at least 90 wt-%HPMC, based on the weight of the shell). Typically, commerciallyavailable HPMC capsules include small amounts of water, colorants (e.g.,TiO₂ and iron oxides), and optionally gelling agents and gellingpromoters. They have relatively low moisture content, making themsuitable for moisture-sensitive materials. Such capsules resist breakageeven at low moisture levels. HPMC capsules typically exhibit lowsolubility in ethanol, particularly in acidic media such as found in thestomach. Encapsulation of the particles of the present disclosure insuch an HPMC capsule shell preferably reduces dose dumping (andimmediate release) of topiramate from the coated particles (see “AlcoholDose Dumping” experiment in the Examples Section).

The chemical stability of capsules of the present disclosure typicallydepends on humidity and/or water activity. Thus, it can be desirable toreduce exposure to excessive moisture during storage. This can be done,for example, by storing the capsules of the present disclosure in acontainer, particularly a sealed container that includes a desiccant. Ifa desiccant is used, the ratio of weight of desiccant to weight offilled capsules can be at least 0.01, or at least 0.1, or at least 0.25,and can be up to 0.9.

Suitable containers include, for example, high density polyethylene(HDPE). Such containers can be bottles with screw caps, or the like.Preferably, such bottles are sealed, particularly induction sealed, inaddition to a boundary layer provided by the screw cap.

Suitable desiccants include, for example, silica gel, bentonite clay,and molecular sieve. Combinations of desiccants can be used if desired.

Capsules of the present disclosure are preferably chemically stable.That is, capsules of the present disclosure retain a potency of at least90% after a given time period of storage in a sealed container at 25° C.and 60% relative humidity (RH). They also demonstrate little or nodecomposition after a given time period such that no more than 2000parts per million (ppm) each of sulfate or sulfamate decompositionproducts are produced (see Examples Section). In this context, the giventime period is preferably at least 12 months (typically, without anypackaging), or at least 24 months (potentially, without any packaging,although packaging, e.g., sealed container and desiccant as describedherein would be preferred to achieve chemical stability for this lengthof time), or at least 36 months (typically, with packaging, e.g., sealedcontainer and desiccant as described herein).

The present disclosure also provides methods of dosing a subject in needthereof. Such dosing could be for the treatment of convulsions (e.g.,convulsions associated with epilepsy). Such dosing could be forprophylactic treatment, for example, of a migraine. Such dosing methodsinclude administering a topiramate capsule. In certain embodiments,once-per-day dosing of the capsule of the present disclosure occurs inthe morning. In certain embodiments, once-per-day dosing of the capsuleof the present disclosure occurs in the evening.

In certain embodiments, the extended-release topiramate capsules of thepresent disclosure, when dosed to a healthy human subject once daily(e.g., in the morning or evening), achieves at steady-state, anAUC_(0-24h), C_(max), and C_(min) in the subject's plasma that arewithin the 80% to 125% bioequivalence criteria compared toimmediate-release topiramate dosed twice per day (where the once-dailydose contains 2× the topiramate active agent as the individualimmediate-release doses).

In this context, two treatments are bioequivalent at steady state (i.e.,they are not different from one another) if the 90% confidence interval(CI) of the least squares geometric mean of one formulation-to-anotherformulation (e.g., capsules of the present disclosure to once-daily dosetopiramate) ratio for each pharmacokinetic (PK) parameter (e.g.,AUC_(0-24h), C_(max), and C_(min)) is completely contained within the80-125% interval.

In certain embodiments, the extended-release topiramate capsules of thepresent disclosure, when dosed to a healthy human subject once daily inthe morning, achieves at steady-state, a reduction of fluctuation indexof at least 15% compared to immediate-release topiramate dosed twice perday. In certain embodiments, the reduction of fluctuation index is atleast 20% compared to immediate-release topiramate dosed twice per day.In certain embodiments, the reduction of fluctuation index is at least25% compared to immediate-release topiramate dosed twice per day.

In certain embodiments, the extended-release topiramate capsules of thepresent disclosure, when dosed to a healthy human subject once daily inthe morning, achieves at steady-state, a C_(min) in the subject's plasmathat is higher than the C_(min) compared to immediate-release topiramatedosed twice per day.

In certain embodiments, the extended-release topiramate capsules of thepresent disclosure, when given as a single-dose to a healthy humansubject, achieves an AUC_(0-inf) of 170 to 210 h·μg/mL within a 95%confidence interval, and a C_(max) of 2 to 4 μg/mL within a 95%confidence interval.

Capsules of the present disclosure demonstrate a reduced level of sideeffects compared to other topiramate products. For example, in certainembodiments, the extended-release topiramate capsules of the presentdisclosure, when dosed once daily to a population of human patientssuffering from epilepsy, achieves a reduction in incidence of at leastone side effect compared to immediate-release topiramate dosed at thesame total daily dose divided twice per day. This comparison is based onthe extended-release topiramate capsules of the present disclosurecompared to placebo, and the immediate-release topiramate (TOPAMAX)compared to placebo. The term “incidence” refers to the percentage ofpatients who experience a new side effect during the study. The at leastone side effect includes somnolence, dizziness, ataxia, disturbance inattention, memory impairment, cognitive disorder, and psychomotorslowing.

LIST OF EXEMPLARY EMBODIMENTS

-   1. An extended-release topiramate capsule comprising:    -   a capsule shell comprising (or consisting essentially of, or        consisting of) a single population of coated particles;        -   wherein each coated particle comprises a core and a coating            thereon;        -   wherein each particle core comprises a homogeneous mixture            comprising topiramate throughout its core; and        -   wherein the coating comprises one or more release            controlling agent(s).-   2. The capsule of embodiment 1 wherein:    -   each particle core comprises a homogeneous mixture comprising:        -   topiramate;        -   one or more filler(s); and        -   one or more binder(s); and    -   the coating comprises:        -   one or more release controlling agent(s);        -   one or more pore former(s); and        -   one or more plasticizer(s).-   3. An extended-release topiramate capsule comprising (or consisting    essentially of, or consisting of):    -   a capsule shell comprising (or consisting essentially of, or        consisting of) a single population of coated particles;        -   wherein each coated particle comprises (or consists            essentially of, or consists of) a core and a coating            thereon;        -   wherein each particle core comprises (or consists            essentially of, or consists of) a homogeneous mixture            throughout its core, the mixture comprising (or consisting            essentially of, or consisting of):            -   40 wt-% to 50 wt-% of topiramate, based on the total                weight of an uncoated particle core;            -   45 wt-% to 55 wt-% of one or more filler(s), based on                the total weight of an uncoated particle core; and            -   3 wt-% to 7 wt-% of one or more binder(s), based on the                total weight of an uncoated particle core;        -   wherein the coating comprises (or consists essentially of,            or consists of):            -   55 wt-% to 65 wt-% of one or more release control                agent(s), based on the total weight of the coating;            -   20 wt-% to 25 wt-% of one or more pore former(s), based                on the total weight of the coating; and            -   10 wt-% to 20 wt-% of one or more plasticizer(s), based                on the total weight of the coating;    -   wherein the particles are coated in an amount sufficient to        provide a weight gain of 8% to 14%.-   4. The extended-release topiramate capsule of any of embodiments 1    through 3 wherein the particles are coated in an amount sufficient    to provide a weight gain of 10% to 12%.-   5. The extended-release topiramate capsule of any of embodiments 1    through 4 wherein the one or more filler(s) is selected from the    group of microcrystalline cellulose, dibasic calcium phosphate,    lactose, tribasic calcium phosphate, mannitol, and combinations    thereof.-   6. The extended-release topiramate capsule of embodiment 5 wherein    the filler is microcrystalline cellulose.-   7. The extended-release topiramate capsule of any of embodiments 1    through 6 wherein the one or more binder(s) is selected from the    group of hydroxypropyl methylcellulose, methylcellulose,    carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl    cellulose, hydroxyethylcellulose, polyvinyl pyrrolidine, starch,    natural gum, and combinations thereof-   8. The extended-release topiramate capsule of embodiment 7 wherein    the binder is hydroxypropyl methylcellulose.-   9. The extended-release topiramate capsule of any of embodiments 1    through 8 wherein the one or more release controlling agent(s) is    selected from the group of ethylcellulose, polyvinyl acetate,    polyacrylate and polymethacrylate, copolymers thereof, and    combinations thereof-   10. The extended-release topiramate capsule of embodiment 9 wherein    the release controlling agent is ethylcellulose.-   11. The extended-release topiramate capsule of any of embodiments 1    through 10 wherein the one or more pore former(s) is selected from    the group of hypromellose, hydroxypropyl cellulose, methylcellulose,    hydroxyethylcellulose, carboxymethylcellulose, sodium    carboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum,    sodium alginate, polyvinylpyrrolidone, crospovidone, sodium starch    glycolate, croscarmellose sodium, starch, mannitol, glucose,    sucrose, fructose, mannose, galactose, sorbitol, dextran, sodium    chloride, potassium chloride, calcium chloride, and combinations    thereof-   12. The extended-release topiramate capsule of embodiment 11 wherein    the pore former is hydroxypropyl methylcellulose.-   13. The extended-release topiramate capsule of any of embodiments 1    through 12 wherein the one or more plasticizer(s) is selected from    the group of diethyl phthalate, triethyl citrate, dibutyl sebacate,    polyethylene glycol, triacetin, tributyl citrate, glycerol,    propylene glycol, and combinations thereof-   14. The extended-release topiramate capsule of embodiment 13 wherein    the plasticizer is diethyl phthalate.-   15. The extended-release topiramate capsule of any of embodiments 1    through 14 wherein each particle core further comprises one or more    stabilizer(s).-   16. The extended-release topiramate capsule of embodiment 15 wherein    the one or more stabilizer(s) is selected from the group of calcium    hydroxide, calcium carbonate, sodium bicarbonate, magnesium    carbonate, and combinations thereof-   17. The extended-release topiramate capsule of embodiment 15 or 16    wherein the one or more stabilizer(s) is present in an amount of 2    wt-% to 10 wt-%, based on the total weight of an uncoated particle    core.-   18. An extended-release topiramate capsule comprising (or consisting    essentially of, or consisting of):    -   a capsule shell comprising (or consisting essentially of, or        consisting of) a single population of coated particles;        -   wherein each coated particle comprises (or consists            essentially of, or consists of) a core and a coating            thereon;        -   wherein each particle core comprises (or consists            essentially of, or consists of) a homogeneous mixture            throughout its core, the mixture comprising (or consisting            essentially of, or consisting of):            -   40 wt-% to 50 wt-% of topiramate, based on the total                weight of an uncoated particle core;            -   45 wt-% to 55 wt-% of one or more filler(s), based on                the total weight of an uncoated particle core; wherein                the one or more filler(s) is selected from the group of                microcrystalline cellulose, dibasic calcium phosphate,                lactose, tribasic calcium phosphate, mannitol, and                combinations thereof; and            -   3 wt-% to 7 wt-% of one or more binder(s), based on the                total weight of an uncoated particle core; wherein the                one or more binder(s) is selected from the group of                hydroxypropyl methylcellulose, methylcellulose,                carboxymethylcellulose, sodium carboxymethylcellulose,                hydroxypropyl cellulose, hydroxyethylcellulose,                polyvinyl pyrrolidine, starch, natural gum, and                combinations thereof;        -   wherein the coating comprises (or consists essentially of,            or consists of):            -   55 wt-% to 65 wt-% of one or more release control                agent(s), based on the total weight of the coating;                wherein the one or more release controlling agent(s) is                selected from the group of ethylcellulose, polyvinyl                acetate, polyacrylate and polymethacrylate, copolymers                thereof, and combinations thereof;            -   20 wt-% to 25 wt-% of one or more pore former(s), based                on the total weight of the coating; wherein the one or                more pore former(s) is selected from the group of                hypromellose, hydroxypropyl cellulose, methylcellulose,                hydroxyethylcellulose, carboxymethylcellulose, sodium                carboxymethylcellulose, polyethylene glycol, guar gum,                xanthan gum, sodium alginate, polyvinylpyrrolidone,                crospovidone, sodium starch glycolate, croscarmellose                sodium, starch, mannitol, glucose, sucrose, fructose,                mannose, galactose, sorbitol, dextran, sodium chloride,                potassium chloride, calcium chloride, and combinations                thereof; and            -   10 wt-% to 20 wt-% of one or more plasticizer(s), based                on the total weight of the coating; wherein the one or                more plasticizer(s) is selected from the group of                diethyl phthalate, triethyl citrate, dibutyl sebacate,                polyethylene glycol, triacetin, tributyl citrate,                glycerol, propylene glycol, and combinations thereof;    -   wherein the particles are coated in an amount sufficient to        provide a weight gain of 8% to 14%.-   19. An extended-release topiramate capsule comprising (or consisting    essentially of, or consisting of):    -   a capsule shell comprising (or consisting essentially of, or        consisting of) a single population of coated particles;        -   wherein each coated particle comprises (or consists            essentially of, or consists of) a core and a coating            thereon;        -   wherein each particle core comprises (or consists            essentially of, or consists of) a homogeneous mixture            throughout its core, the mixture comprising (or consisting            essentially of, or consisting of):            -   40-50 wt-% of topiramate, based on the total weight of                an uncoated particle core;            -   45-55 wt-% of microcrystalline cellulose, based on the                total weight of an uncoated particle core; and            -   3-7 wt-% of hydroxypropyl methylcellulose, based on the                total weight of an uncoated particle core;        -   wherein the coating comprises (or consists essentially of,            or consists of):            -   55-65 wt-% of ethylcellulose, based on the total weight                of the coating;            -   20-25 wt-% of hydroxypropyl methylcellulose, based on                the total weight of the coating; and            -   10-20 wt-% of diethyl phthalate, based on the total                weight of the coating;    -   wherein the particles are coated in an amount sufficient to        provide a weight gain of 8% to 14%.-   20. An extended-release topiramate capsule comprising (or consisting    essentially of, or consisting of):    -   a capsule shell comprising (or consisting essentially of, or        consisting of) a single population of coated particles;        -   wherein each coated particle comprises (or consists            essentially of, or consists of) a core and a coating            thereon;        -   wherein each particle core comprises (or consists            essentially of, or consists of) a homogeneous mixture            throughout its core, the mixture comprising (or consisting            essentially of, or consisting of):            -   44-46 wt-% of topiramate, based on the total weight of                an uncoated particle core;            -   48-52 wt-% of microcrystalline cellulose, based on the                total weight of an uncoated particle core; and            -   4-6 wt-% of hydroxypropyl methylcellulose, based on the                total weight of an uncoated particle core;        -   wherein the coating comprises (or consists essentially of,            or consists of):            -   60-62 wt-% of ethylcellulose, based on the total weight                of the coating;            -   22-24 wt-% of hydroxypropyl methylcellulose, based on                the total weight of the coating; and            -   15-18 wt-% of diethyl phthalate, based on the total                weight of the coating;    -   wherein the particles are coated in an amount sufficient to        provide a weight gain of 10-12%.-   21. The extended-release topiramate capsule of any of embodiments 1    through 20 which, when dosed to a healthy human subject once daily    (e.g., in the morning or evening), achieves at steady-state, an    AUC_(0-24h), C_(max), and C_(min) in the subject's plasma that are    within the 80% to 125% bioequivalence criteria compared to    immediate-release topiramate dosed twice per day.-   22. The extended-release topiramate capsule of any of embodiments 1    through 21 which, when dosed to a healthy human subject once daily    in the morning, achieves at steady-state, a reduction of fluctuation    index of at least 15% compared to immediate-release topiramate dosed    twice per day.-   23. The extended-release topiramate capsule of embodiment 22 which,    when dosed to a healthy human subject once daily in the morning,    achieves at steady-state, a reduction of fluctuation index of at    least 20% compared to immediate-release topiramate dosed twice per    day.-   24. The extended-release topiramate capsule of embodiment 23 which,    when dosed to a healthy human subject once daily in the morning,    achieves at steady-state, a reduction of fluctuation index of at    least 25% compared to immediate-release topiramate dosed twice per    day.-   25. The extended-release topiramate capsule of any of embodiments 1    through 24 which, when dosed to a healthy human subject once daily    in the morning, achieves at steady-state, a C_(min) in the subject's    plasma that is higher than the C_(min) compared to immediate-release    topiramate dosed twice per day.-   26. The extended-release topiramate capsule of any of embodiments 1    through 25 which, when given as a single-dose to a healthy human    subject, achieves an AUC_(0-inf) of 170 to 210 h·μg/mL within a 95%    confidence interval, and a C_(max) of 2 to 4 μg/mL within a 95%    confidence interval.-   27. The extended-release topiramate capsule of any of embodiments 1    through 26 which, when dosed once daily to a population of human    patients suffering from epilepsy, achieves a reduction in incidence    of at least one side effect compared to immediate-release topiramate    dosed at the same total daily dose divided twice per day.-   28. The extended-release topiramate capsule of any of embodiments 1    through 27 which is chemically stable for at least 12 months.-   29. The extended-release topiramate capsule of embodiment 28 which    is chemically stable for at least 24 months.-   30. The extended-release topiramate capsule of embodiment 29 which    is chemically stable for at least 24 months when stored in a sealed    container with desiccant.-   31. The extended-release topiramate capsule of embodiment 30 which    is chemically stable for at least 36 months when stored in a sealed    container with desiccant.-   32. The extended-release topiramate capsule of any of embodiments 1    through 31 which is free of an immediate release component.-   33. The extended-release topiramate capsule of any of embodiments 1    through 32 wherein the coated particles have a sphericity of at    least 0.7.-   34. The extended-release topiramate capsule of any of embodiments 1    through 33 wherein the coated particles have a particle size of at    least 500 μm.-   35. The extended-release topiramate capsule of any of embodiments 1    through 34 wherein the coated particles have a particle size of up    to 1300 μm.-   36. The extended-release topiramate capsule of any of embodiments 1    through 35 wherein the capsule shell comprises hydroxypropyl    methylcellulose or gelatin.-   37. The extended-release topiramate capsule of embodiment 36 wherein    the capsule shell is a hydroxypropyl methylcellulose capsule.-   38. A container comprising an extended-release topiramate capsule of    any of embodiments 1 through 37 and desiccant.-   39. The container of embodiment 38 wherein the ratio of weight of    desiccant to weight of filled capsules is at least 0.01.-   40. The container of embodiment 38 or 39 wherein the ratio of weight    of desiccant to weight of filled capsules is up to 0.9.-   41. The container of any of embodiments 38 through 40 wherein the    desiccant is selected from silica gel, bentonite clay, molecular    sieve, and combinations thereof.-   42. A method of dosing a subject in need thereof, the method    comprising administering an extended-release topiramate capsule of    any of embodiments 1 through 37 once daily to the subject.-   43. The method of embodiment 42 wherein the administering occurs    once daily in the morning.-   44. The method of embodiment 42 wherein the administering occurs    once daily in the evening.-   45. The method of any of embodiments 42 through 44 wherein the    dosing is for the treatment of convulsions.-   46. The method of any of embodiments 42 through 44 wherein the    dosing is for the prophylactic treatment of a migraine.

EXAMPLES Process and Formulations

-   -   1. High Shear Granulation: The core bead components listed in        the table below are added to the high shear granulator and        blended. After the pre-mix step, Purified Water is added to the        high shear granulator and the mixture kneaded to create a wet        granulation.    -   2. Extrusion: The wet granulation is then fed at a specified        rate into a twin dome extruder equipped with dome dies having        0.8 mm pores to form an extrudate.    -   3. Spheronization: Portions of the extrudate from the extruder        are weighed out and processed, for a specified time sufficient        to form spherical particles (i.e., beads), in a spheronizer        equipped with a 2×2 mm friction plate.    -   4. Drying: The wet spherical particles are dried in a fluid bed        processor to a moisture content of not more than (NMT) 3.0% w/w,        as determined by an in-process loss-on-drying analysis.    -   5. Sizing: The dried particles are sized using a 14-mesh and a        30-mesh sieve (Market Grade mesh screen). Material passing        through the 14-mesh sieve, but retained on the 30-mesh sieve is        taken into the subsequent coating step.    -   6. Coating: The dried, sized, uncoated beads are coated in a        Würster fluidized bed processor to a desired coating weight gain        using the coating composition listed in the table below.    -   7. Sizing: Following coating, the beads are sized using a        14-mesh and a 30-mesh sieve (Market Grade mesh screen). Material        passing through the 14-mesh sieve, but retained on the 30-mesh        sieve is taken into the subsequent encapsulation step.    -   8. Encapsulation: Using a suitable encapsulator, appropriate        amounts of coated beads are filled into appropriate size        capsules to yield the different strengths of the product. The        encapsulated product is also run through a capsule polisher,        metal detector, and weight checker.

Formulation designation A B Coating Weight Gain** 12% w/w 10% w/w Coreparticle components (% w/w, based on weight of the core) Topiramate 4545 Microcrystalline Cellulose 50 50 Hypromellose 2910 5 5 Coatingcomponents*** (% w/w, based on weight of the coating) Ethylcellulose60.86 60.86 Hypromellose 2910 22.56 22.56 Diethyl Phthalate 16.58 16.58Dehydrated Alcohol* NA NA Purified Water* NA NA *Removed duringprocessing. **Weight gain is defined as the theoretical weight gainafter coating of a population of uncoated particles, assuming 100%coating efficiency. ***The solids content (non-volatile components,i.e., ethylcellulose, hypromellose 2910 and diethyl phthalate) of thecoating solution was 7.5% w/w for B and 6% w/w for A. The ratio ofDehydrated Alcohol to Purified Water is about 3.7:1 on a weight basis.PK Results

In clinical studies, the extended-release topiramate capsules ofFormulation A, when given as a single-dose to a healthy human subject,achieved an AUC_(0-inf) of 173.9 to 200.1 h·μg/mL within a 95%confidence interval, and a C_(max) of 2.64 to 3.16 μg/mL within a 95%confidence interval.

In clinical studies, the extended-release topiramate capsules ofFormulation B, when given as a single-dose to a healthy human subject,achieved an AUC_(0-inf) of 179.7 to 204.3 h·μg/mL within a 95%confidence interval, and a C_(max) of 2.94 to 3.43 μg/mL within a 95%confidence interval.

Adverse Event Evaluation

In clinical studies, the extended-release topiramate capsules of thepresent disclosure, when dosed to patients with epilepsy (morespecifically, as adjunctive treatment in patients with refractorypartial onset seizure with or without generalization) once daily,achieved a reduction in incidence of at least one side effect comparedto immediate-release topiramate dosed at the same total daily dosedivided twice per day.

This comparison is based on the extended-release topiramate capsules ofthe present disclosure compared to placebo, and the immediate-releasetopiramate (TOPAMAX) compared to placebo. Each being compared to placebo(as opposed to each other), this evaluation demonstrated that theextended-release topiramate capsules of the present disclosure achieve areduction in at least one side effect (e.g., somnolence, dizziness,ataxia, disturbance in attention, memory impairment, cognitive disorder,and psychomotor slowing).

Alcohol Dose Dumping

Capsules of the present disclosure, which included an ethanol-solubleparticle coating, were evaluated in vitro for dose dumping in ethanolusing a USP apparatus 1 (baskets) operating at 100 revolutions perminute (rpm) with a pH 1.2 HCl buffer containing 5 to 40% v/v (volume byvolume) ethanol. There was no evidence of immediate release orunacceptable acceleration of release of the topiramate.

Sulfate/Sulfamate Method

Sulfate and Sulfamate degradation products were measured utilizing anion chromatography (IC) method with ion suppression conductivitydetection. The chromatographic system used an Alltech Novosep A-2,250×4.0 mm, 5-μm particle size column maintained at 43° C. The flow rateof the 3.6 mM sodium carbonate mobile phase was 1.0 mL/min. A 7 mg/mLsolution of topiramate in water containing 10% acetonitrile was preparedfrom particles (removed from a capsule of the present disclosure) usingsonication and mixing to extract the sulfate and sulfamate degradationproducts. Particles within the capsules of the present disclosuredemonstrated little or no decomposition after a given time period, suchthat no more than 2000 parts per million (ppm) each of sulfate orsulfamate degradation products were produced.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this disclosure will become apparent tothose skilled in the art without departing from the scope and spirit ofthis disclosure. It should be understood that this disclosure is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the disclosureintended to be limited only by the claims set forth herein as follows.

What is claimed is:
 1. An extended-release topiramate capsulecomprising: a capsule shell comprising a single population of coatedparticles; wherein each coated particle comprises a core and a coatingthereon; wherein each particle core comprises a homogeneous mixturethroughout its core, the mixture comprising: 40 wt-% to 50 wt-% oftopiramate, based on the total weight of an uncoated particle core; 45wt-% to 55 wt-% of one or more filler(s), based on the total weight ofan uncoated particle core; and 3 wt-% to 7 wt-% of one or morebinder(s), based on the total weight of an uncoated particle core;wherein the coating comprises components including: one or more releasecontrolling agent(s); one or more pore former(s); and one or moreplasticizer(s); wherein the coating components are present in amountsthat provide an extended release topiramate capsule; wherein, when asingle dose is given to a healthy human subject, an AUC_(0-inf) of 170to 210 h·μg/mL within a 95% confidence interval, and a C_(max) of 2 to 4μg/mL within a 95% confidence interval are achieved in the subject'splasma.
 2. The extended-release topiramate capsule of claim 1 which,when dosed to a healthy human subject once daily, achieves atsteady-state, an AUC_(0-24h), C_(max), and C_(min) in the subject'splasma that are within the 80% to 125% bioequivalence criteria comparedto immediate-release topiramate dosed at the same total daily dosedivided twice per day.
 3. The extended-release topiramate capsule ofclaim 1 which, when dosed to a healthy human subject once daily in themorning, achieves at steady-state, a reduction of fluctuation index ofat least 15% compared to immediate-release topiramate dosed at the sametotal daily dose divided twice per day.
 4. The extended-releasetopiramate capsule of claim 1 which, when dosed to a healthy humansubject once daily in the morning, achieves at steady-state, a C_(min)in the subject's plasma that is higher than the C_(min) compared toimmediate-release topiramate dosed at the same total daily dose dividedtwice per day.
 5. The extended-release topiramate capsule of claim 1which, when dosed once daily to a population of human patients sufferingfrom epilepsy, achieves a reduction in incidence of at least one sideeffect compared to immediate-release topiramate dosed at the same totaldaily dose divided twice per day.
 6. The extended-release topiramatecapsule of claim 1 wherein the particles are coated in an amountsufficient to provide a weight gain of 2% to 30%.
 7. Theextended-release topiramate capsule of claim 1 which is chemicallystable for at least 12 months.
 8. The extended-release topiramatecapsule of claim 1 wherein the capsule shell is a hydroxypropylmethylcellulose capsule.
 9. The extended-release topiramate capsule ofclaim 1 which is free of an immediate-release component.
 10. Theextended-release topiramate capsule of claim 1 wherein the one or morefiller(s) is selected from the group of microcrystalline cellulose,dibasic calcium phosphate, lactose, tribasic calcium phosphate,mannitol, and combinations thereof.
 11. The extended-release topiramatecapsule of claim 10 wherein the filler is microcrystalline cellulose.12. The extended-release topiramate capsule of claim 1 wherein the oneor more binder(s) is selected from the group of hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose,polyvinyl pyrrolidine, starch, natural gum, and combinations thereof.13. The extended-release topiramate capsule of claim 12 wherein thebinder is hydroxypropyl methylcellulose.
 14. The extended-releasetopiramate capsule of claim 1 wherein the one or more releasecontrolling agent(s) is selected from the group of ethylcellulose,polyvinyl acetate, polyacrylate and polymethacrylate, copolymersthereof, and combinations thereof.
 15. The extended-release topiramatecapsule of claim 14 wherein the release controlling agent isethylcellulose.
 16. The extended-release topiramate capsule of claim 1wherein the one or more pore former(s) is selected from the group ofhypromellose, hydroxypropyl cellulose, methylcellulose,hydroxyethylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum,sodium alginate, polyvinylpyrrolidone, crospovidone, sodium starchglycolate, croscarmellose sodium, starch, mannitol, glucose, sucrose,fructose, mannose, galactose, sorbitol, dextran, sodium chloride,potassium chloride, calcium chloride, and combinations thereof.
 17. Theextended-release topiramate capsule of claim 16 wherein the pore formeris hydroxypropyl methylcellulose.
 18. The extended-release topiramatecapsule of claim 1 wherein the one or more plasticizer(s) is selectedfrom the group of diethyl phthalate, triethyl citrate, dibutyl sebacate,polyethylene glycol, triacetin, tributyl citrate, glycerol, propyleneglycol, and combinations thereof.
 19. The extended-release topiramatecapsule of claim 18 wherein the plasticizer is diethyl phthalate. 20.The extended-release topiramate capsule of claim 1 wherein each particlecore further comprises one or more stabilizer(s) selected from the groupof calcium hydroxide, calcium carbonate, sodium bicarbonate, magnesiumcarbonate, and combinations thereof.
 21. An extended-release topiramatecapsule comprising: a capsule shell comprising a single population ofcoated particles; wherein each coated particle comprises a core and acoating thereon; wherein each particle core comprises a homogeneousmixture throughout its core, the mixture comprising: 40 wt-% to 50 wt-%of topiramate, based on the total weight of an uncoated particle core;45 wt-% to 55 wt-% of one or more filler(s), based on the total weightof an uncoated particle core; wherein the one or more filler(s) isselected from the group of microcrystalline cellulose, dibasic calciumphosphate, lactose, tribasic calcium phosphate, mannitol, andcombinations thereof; and 3 wt-% to 7 wt-% of one or more binder(s),based on the total weight of an uncoated particle core; wherein the oneor more binder(s) is selected from the group of hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose,polyvinyl pyrrolidine, starch, natural gum, and combinations thereof;wherein the coating comprises components including: one or more releasecontrol agent(s) selected from the group of ethylcellulose, polyvinylacetate, polyacrylate and polymethacrylate, copolymers thereof, andcombinations thereof; one or more pore former(s) selected from the groupof hypromellose, hydroxypropyl cellulose, methylcellulose,hydroxyethylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum,sodium alginate, polyvinylpyrrolidone, crospovidone, sodium starchglycolate, croscarmellose sodium, starch, mannitol, glucose, sucrose,fructose, mannose, galactose, sorbitol, dextran, sodium chloride,potassium chloride, calcium chloride, and combinations thereof; and oneor more plasticizer(s) selected from the group of diethyl phthalate,triethyl citrate, dibutyl sebacate, polyethylene glycol, triacetin,tributyl citrate, glycerol, propylene glycol, and combinations thereof;wherein the coating components are present in amounts that provide anextended release topiramate capsule; wherein, when a single dose isgiven to a healthy human subject, an AUC_(0-inf) of 170 to 210 h·μg/mLwithin a 95% confidence interval, and a C_(max) of 2 to 4 μg/mL within a95% confidence interval are achieved in the subject's plasma.
 22. Theextended-release topiramate capsule of claim 21 which, when dosed to ahealthy human subject once daily, achieves at steady-state, anAUC_(0-24h), C_(max), and C_(min) in the subject's plasma that arewithin the 80% to 125% bioequivalence criteria compared toimmediate-release topiramate dosed at the same total daily dose dividedtwice per day.
 23. The extended-release topiramate capsule of claim 21which, when dosed to a healthy human subject once daily in the morning,achieves at steady-state a reduction of fluctuation index of at least15% compared to immediate-release topiramate dosed at the same totaldaily dose divided twice per day.
 24. The extended-release topiramatecapsule of claim 21 which, when dosed to a healthy human subject oncedaily in the morning, achieves at steady-state a C_(min) in thesubject's plasma that is higher than the C_(min) compared toimmediate-release topiramate dosed at the same total daily dose dividedtwice per day.
 25. The extended-release topiramate capsule of claim 21which, when dosed once daily to a population of human patients sufferingfrom epilepsy, achieves a reduction in incidence of at least one sideeffect compared to immediate-release topiramate dosed at the same totaldaily dose divided twice per day.